Water → HCID 70983262, compound

HRID 1479196Notes

Reaction equation

HRID 1479196 reaction equation
[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]([CH3:39])[CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([N:36]4[CH2:37][CH2:38][CH:33]([N:32]([CH3:39])[CH3:31])[CH2:34][CH2:35]4)=[CH:25][CH:24]=3)=[N:17][NH:18]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 4

HCID 962WaterHCID 417391N,N-Dimethylpiperidin-4-amineHCID 2733832Lithium HexamethyldisilazideHCID 70982294HCID 70982294, compound

Product 1

HCID 70983262HCID 70983262, compoundYield 73%

Reagents, catalysts & solvents 3

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylCatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent2×

Procedure

A solution of N-[6-(2-benzyloxy-ethoxy)-1H-indazol-3-yl]-4-bromo-benzamide (1.3 g, 2.79 mmol) and 4-dimethylamino-piperidine (1.18 ml, 8.37 mmol) in dry THF (20 ml) was degassed by three vacuum-argon atmosphere cycles and treated at r.t., under argon atmosphere, with Pd2(dba)3 (50 mg), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (50 mg) and 1M LiHMDS in THF (22.3 ml, 22.3 mmol). The reaction mixture was heated to reflux and stirred for 15 min then cooled to r.t., poured into 200 ml of water and extracted with 200 ml of EtOAc. The organic layer was separated, dried over sodium sulfate and evaporated to dryness. The crude residue was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Varian SF40-120 g) using DCM as eluant A and DCM/7N NH3 in MeOH 10:1 as eluant B. Elution with a gradient from A/B 100:0 to 0:100 over 10 CV, followed by an isocratic elution with eluant B (5 CV), gave a yellow solid that was triturated with EtOAc (15 ml), filtered, washed with EtOAc and dried affording 1.04 g (yield: 73%) of the title compound as a white solid.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux
  3. extractionextracted with 200 ml of EtOAc
  4. customThe organic layer was separated
  5. dry with materialdried over sodium sulfate
  6. customevaporated to dryness
  7. customThe crude residue was purified by chromatography (Biotage SP1 Flash Purification system) on a silica gel cartridge (Varian SF40-120 g)
  8. washElution with a gradient from A/B 100:0 to 0:100 over 10 CV
  9. washfollowed by an isocratic elution with eluant B (5 CV)
  10. customgave a yellow solid
  11. customthat was triturated with EtOAc (15 ml)
  12. filtrationfiltered
  13. washwashed with EtOAc
  14. customdried

Sources & evidence

ORD record
ord-26744b2071824c30ae99eb1b546d6e09
Source dataset
uspto-grants-2016_08
Patent number
US09408850B2

Reaction notes

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